Prevention of corticosteroid side effects



United States Patent US. Cl. 424-240 Claims ABSTRACT OF THE DISCLOSURE This invention relates to the prevention of corticosteroid side effects which would normally occur by the administration of corticosteroids (e.g. gluco-corticoids) for various conditions for which the same have been found to be useful, the prevention of the side effects which normally occur being accomplished by administering with, just prior to or just after the administration of the corticosteroid of an effective amount of a beta-(Z- or 4- pyridyl-alkyl amine or a similarly acting substance. It has been found that for reasons which are not yet fully explained but for which I have some theoretical explanations, that substances like beta-(Z- or 4-pyridylalkyl) amines permit the corticosteroid to act in its normal manner for alleviation of the condition for which the same is administered, but prevent the occurrence of side effects which normally accompany the administration of the corticosteroid.

BACKGROUND OF THE INVENTION The use of corticosteroids for many conditions such as acute inflammatory and allergic diseases of the eye, skin and mucosa, rheumatoid arthritis, bronchial asthma, ulcerative colitis, and other conditions too numerous to mention, has become increasingly more important in recent years. The major limitation as to the use of such corticosteroids, e.g. hydrocortisone, for such purposes has been the high incidence of untoward side effects which accompany such administration. In fact the use of corticosteroids to an even greater extent than has been presently possible has been limited mainly by these undesired side effects. Attempts have been made to reduce the side effects of the corticosteroids by making various steroid derivatives. However, while these steroid derivatives have, in some cases, resulted in a higher degree of activity per molecule, such activity on a biological unit per biological unit basis, remains essentially parallel in side effects. It can generally be stated that no satisfactory means have yet been achieved for reducing the undesired side effects of the corticosteroids.

Among the side effects which occur upon administration of corticosteroids are iatrogenic (or physician induced) Cushings disease, sodium retention and potassium excretion with edema, hypertension, hyperglycemia, glycosuria, etc. In many cases the side effects of the administration to the corticosteroids are so great that continued use thereof becomes impossible despite the need for the corticosteroid desired effect. Thus, it is often necessary to give doses below the desired dose and likewise it is often necessary to discontinue treatment with the corticosteroid when continued treatment would be desirable except for the undesired side effects which take place.

SUMMARY OF THE INVENTION Generally speaking in accordance with the invention a method is provided for preventing the side effects of a corticosteroid which would otherwise occur upon administration of the same by administering to the subject which is to receive the corticosteroid either at the time c Ce of administration of the corticosteroid or shortly before or shortly after such administration an agent which I have found has the effect of permitting the corticosteroid to act in its desired manner while at the same time preventing the undesired side effects which would otherwise occur upon simple administration of the corticosteroid.

It is accordingly a primary object of the present invention to provide for the prevention of side effects from the administration of corticosteroids while achieving the desired main effect thereof.

It is yet another object of the present invention to provide compositions including a corticosteroid which by itself would cause undesired side effects, and also including an agent which prevents the undesired side effects of corticosteroid from occuring.

It is yet a further object of thep resent invention to provide superior compositions for the treatment of conditions which are treated by corticosteroids, these compositions being superior because they can be given in larger doses and over longer periods of time without undesired side effects occurring.

Other objects and advantages of the present invention will be apparent from a further reading of the specification and of the appended claims.

With the above and other objects in view, the present invention mainly comprises a method of administering corticosteroids while preventing the occurrence of -undesired side elfects from such administration, by administering simultaneously with, just prior to or shortly after the administration of the corticosteroid at least one member selected from the group consisting of beta- (Z-pyridylalkyl)-amines, beta (4 pyridyl alkyl) amines, 1- (2'-pyridyl) 2,3 cis or trans dicarboxylic acid cyclobutanes, 1-(4'-pyridyl) 2,3 cis or trans dicarboxylic acid cyclobutanes, alpha-picolinic acid di loweralkylamides, and non-toxic acid addition salts of any of them.

This invention is applicable to all corticosteroids and known derivatives thereof which can be used for the treatment of anti-inflammatory and other conditions. Among these steroids, which are mentioned for exemplatory purposes only, are cortisone (including derivatives thereof such as cortisone phosphate, etc.), hydrocortisone (and derivatives thereof such as the 2l-sodiun1 succinate, etc.), prednisone, dexamethasone, ACTH, corticosterone, l1- dehydrocorticosterone, ll-desoxycorticosterone, aldosterone, etc. These corticosteroids are administered for many purposes such as the treatment of Addisons disease, hypopituitarism, adrenal hyperphasia, collagen diseases such as rheumatoid arthritis rheumatic fever and rheumatic carditis, diseases having an allergy basis such as bronchial asthma, allergic vasomotor rhinitis, inflammatory diseases of the eye, pulmonary fibrosis, sarcoidosis, diseases of the skin, acute gouty arthritis, etc.

The specific amount of the corticosteroid which is administered depends on the specific corticosteroid and. on the condition for which it is administered. The present invention is applicable to any effective amount. Thus, for example, in the case of cortisone the dosage may be 2.5 to mg. orally, 5 to 300 mg. I.M., up to 100 mg. I.V., and 0.5-2.5% suspension or ointment for topical administration. In the case of administration to cattle for ketosis the amount may be 1.0-1.5 g. I.M., and to dogs for arthristis the amount may be 25-75 mg. orally. In the case of hydrocortisone the dosage is generally about of the dosage of cortisone. In the case of prednisone the oral dose is about 20 to 60 mg. per day as a suppressive dose, which is gradually decreased until the optimum maintenance dose is determined. In the case of dexamethasone which is approximately seven times as potent as prednisolone and 20 to 35 times as potent as hydrocortisone, the dose is about 0.5 to 1.5 mg. orally and about a 0.1% 10- tion for topical administration. As indicated above, the present invention is applicable to the use of any effective dose of any of these and other corticosteroids.

In accordance with the present invention an agent is administered, of the type mentioned above, and of which more specific examples will be given below, either simultaneously with the corticosteroid, shortly prior thereto or shortly after administration of the corticosteroid, which agent has, for some as yet unexplained reason, the ability of preventing manifestation of the undesired side effects of the corticosteroid without interfering with the main action thereof. An effective amount of the agent is administered, the specific effective amount varying somewhat depending upon the particular agent, and the administration thereof is preferably oral.

The most preferred compounds for preventing the undesired side effects of the corticosteroids are the beta-(2- pyridyl-alkyl)-amines, beta-(4-pyridyl-alkyl)-amines and the non-toxic acid addition salts thereof. The most preferred of these compounds are those wherein the akyl is a lower alkyl such as methyl and/or ethyl, e.g. beta-(2- pyridyl -ethylmethyl amine, beta- (4-pyridyl)-ethylmethyl amine, 1-(2-pyridyl)-2-methylamine propane, and their non-toxic acid addition salts thereof such as the hydrochloride, tartrate, fumarate, gluconate, etc.

The beta-(Z- or 4-pyridylalkyl)-amines are preferably administered in an amount of about 2-50 mg. per day, preferably in an amount of about 445 mg. per day, and most preferably in an amount of about 12-45 mg. per day. The dosage is preferably applied in a unit dosage of about 2-15 mg. per day administered 3-4 times a day. These compounds may be administered either orally or by injection.

Other pyridylalkyl amines and pyridylalkyl amine acid addition salts include 2-(2-(N,N-diethylamino) ethyl) pyridine monofumarate; 2-(2-(N,-ethylamino) ethyl) pyridine monofumarate; 2-(2-(amino) ethyl) pyridine monofumarate; 4-(2'-(amino) ethyl) pyridine monofumarate; 4-(2'-(methylamino) ethyl) pyridine monofumarate; beta-(2-pyridyl)-ethyldiethylamine hydrochloride; 1- (Z-pyridyl)-2-rnethylaminopropane hydrochloride; and beta- Z-pyridyl -ethylamine hydrochloride.

Among the pyridyl dicarboxylic acid cyclobutanes may be mentioned 1-(2-pyridyl)-2,3-trans dicarboxylic acid cyclobutane; l(4-pyridyl)-2,3-trans dicarboxylic acid cyclobutane; 1-(2'-pyridyl)-2,3-cis dicarboxylic acid cyclobutane; and 1(4'-pyridyl)-2,3-cis dicarboxylic acid cyclobutane.

Among the alpha-picolinic acid di-loweralkyl amides may be mentioned alpha-picolinic acid diethylamide; alpha-picolinic acid dimethylamide; and of course the acid addition salts thereof such as the hydrochloride, sulfate, etc. The amount of these compounds which is generally used is between about 0.1-1 mg. administered three times a day.

While this invention is not meant to be limited to any specific theory as to how or why the undesired side effects of the corticosteroids are prevented in accordance with thi invention, the following theory is given in the hope that it will help others in further research in this field.

It is believed that the corticosteroids function by passive attachment to microvascular smooth muscle cells and interference with the dilator action of histamine. Histamine is normally formed in small amounts within the smooth muscle cells. However, the rate of histamine production is increased by stressful stimuli of either a local or systemic nature. A localized activation of histamine synthesis, resulting from local tissue irritation, mediates the early phases of inflammation. A general increase in histamine synthesis occurs when a stress, e.g. extensive injury, causes release of the constrictor substancses adrenaline and noradrenaline.

Thus, corticosteroid antagonism of the increased histamine effect in stress could underly the essential stress function of these hormones, the susceptibility of adrenaldeficient animals to stress, and the large variability in corticosteroid requirements. corticosteroid antagonism of increased local histamine effects might be the underlying factor in the anti-inflammatory effect of the corticosteroid.

It would therefore seem that the harmful side effects of corticosteroid therapy may arise from the tendency of those hormones to close microvascular sphincters by opposing the normal dilator action of histamine. As a result, corticosteroid dosing reduces capillary blood flow, tissues become undernourished, and widespread abnormalities in cell chemistry and function develop, the side effects of the corticosteroid therapy being manifested as a result.

The agents which are used according to the present invention to prevent the manifestation of the corticosteroid side effect apparently counteract the tendency of the hormones to reduce capillary blood fiow and by increasing this blood fiow therefore prevent the corticosteroid side effects from occurring, while at the same time not interfering with the anti-inflammatory effect of the corticosteroid. These agents according to the present invention have, in addition, low toxicity and, of considerable importance, are effective upon oral administration.

DESCRIPTION OF PREFERRED EMBODIMENTS The following examples are given to further illustrate the present invention. The scope of the invention is not, however, meant to be limited to the specific details of the examples.

EXAMPLE 1 A stressed adrenalectomized rat is injected with 5 mg. of hydrocortisone. Increased closure time of hepatic microvascular sphincters results in an abnormally rapid perfusion of those sinusoids remaining open. This process triggers metabolic activation of the overfed hepatic cells and the generalized non-specific hepatic anabolism characteristic of the corticosteriod treated animal arises.

Another stressed adrenalectomized rat is injected with the same amount of hydrocortisone plus 1 mg. of beta- (Z-pyridyl) methylethylamine hydrochloride betahistine hydrochloride in physiological salt solution. Due to the restoration of the open and closed sphincters, the degree of side effects is considerably lessened.

EXAMPLE 2 Tablets are prepared by usual tabletting procedure, each tablet containing:

Cortisone 10 Beta- Z-pyridyl) -ethylmethylamine hydrochloride 5 Calcium carbonate, q.s 200 The above tablet can be administered for any purpose for which cortisone is orally administered to achieve the 4 full effect of the cortisone with reduced danger of the undesired side effects.

EXAMPLE 3 EXAMPLE 4 Tablets are prepared by the usual tabletting procedure,

each tablet containing:

Mg. Prednisone 5 Beta- Z-pyridyl) -ethylamine hydrochloride 2 Lactose, g.s 250 The above tablet can be freely used in all conditions calling for the use of prednisone, with considerably reduced danger of the undesired side effects of the prednisone.

EXAMPLE A patient having an acute inflammatory condition of the mucosa is treated by daily injections of 100 mg. of cortisone acetate administered intramuscularly. The patient is given 12 mg. of beta-(Z-pyridyl)-ethy1diethylamine hydrochloride four times a day by oral ingestion of tablets containing the same. No untoward side effects of the cortisone are manifest after several Weeks of such treatment.

EXAMPLE 6 Ophthalmic eye drops are prepared having the following composition per cubic centimeter:

Dexamethasone sodium phosphate, mg 1 Beta-(Z-pyridyl) methlethylamine hydrochloride, mg. 2 Sodium bisulfite (preservative), percent mg. O. 32 Water for injection, g.s. cc. 1

EXAMPLE 7 An ointment preparation is made of the following composition:

Hydrocortisone acetate, mg. 25 Beta-(2-pyridyl) methylethylamine hydrochloride mg. 5

Bland, non-irritating base of anhydrous lanoline, white petrolatum and mineral oil, q.s,

gram

The above ointment may be applied topically to the skin for control of local inflammatory conditions.

It is believed that from the foregoing adaptations and variations of the invention can be made without departing from the essential characteristics thereof. Such adaptationsand variations are meant to be comprehended within the scope of the appended claims.

I claim:

1. Method of reducing manifestation of side effects occurring upon placing a subject under corticosteroid therapy, which comprises administering to said subject while the same is under effective therapy of a. corticosteroid having an anti-inflammatory action and having a tendency to reduce capillary blood flow an effective amount of at least one member selected from the group consisting of beta-(Z-pyridyl-alkyl)-amines, beta-(4- pyridyl-a1kyl)-amines, 1 (2'-pyridyl)-2,3-cis-dicarboxylic acid cyclobutane, 1-(2' pyridyl) 2,3 trans-dicarboxylic acid cyclobutane, 1-(4'-pyridy1)-2,3-cis-dicarboxylic acid cyclobutane, 1-(4'-pyridyl) 2,3 trans-dicarboxylic acid cyclobutane, alpha-picolinic acid di-loweralkyl-amides and non-toxic acid addition salts thereof, sufficient to increase capillary blood flow and thereby to counteract the capillary blood flow reducing tendency of said corticosteroid.

2. Method according to claim 1 wherein said member is selected from the group consisting of beta-(2-pyridy1 loweralkyl)-amines, beta-(4-pyridyl-loweraylkyl)-amines and non-toxic acid addition salts thereof.

3. Method according to claim 2 wherein said member is administered orally.

4. Method according to claim 3 wherein said member is administered in an amount of about 2-50 mg. per day.

5. Corticosteroid composition with reduced tendency of causing corticosteroid side effects, said composition comprising an effective amount of a corticosteroid having an anti-inflammatory action and having a tendency to reduce capillary blood flow and an effective amount of at least one member selected from the group consisting of beta- (2-pyridyl-alkyl -amines, beta-(4pyridyl-alkyl -amines, 1-(2-pridyl)-2,3-cis-dicarboxylic acid cyclobutane, 1-(2'- pyridyl)-2,3-trans-dicarboxylic acid cyclobutane, 1-(4'- pyridyl)-2,3-cis-dicarboxylic acid cyclobutane, 1-(4- pyridyl)-2,3-trans-dicarboxylic acid cyclobutane, alphapicolinic acid di-loweralkyl-amides and non-toxic acid addition salts thereof, sufficient to increase capillary blood flow.

6. Composition according to claim 5 wherein said member is selected from the group consisting of beta-(2- pyridyl-loweralkyl -arnines, beta-(4-pyridyl-loweralkyl) amines and non-toxic acid addition salts thereof.

7. Composition according to claim 6 wherein said member is present in an amount of about 2-15 mg.

8. Composition according to claim 7 wherein said composition is in a form of oral administration.

9. Composition according to claim 5 wherein said composition is in a form for oral admistration.

10. Composition according to claim 5 in injectable form wherein said corticosteriod and said member are distributed in an injectable liquid.

References Cited UNITED STATES PATENTS 2,794,763 6/1957 Pinson 'et al. 424-240 3,105,010 9/ 1963 Perlman 424240 XR 3,284,304 11/1966 Montandravd 424240 XR 3,415,833 12/1968 Fossel 260-295 SHEP K. ROSE, Primary Examiner 

